This is an exploratory research grant that develops a novel therapeutic approach for treating African trypanosomiasis, a fatal human parasitic disease that has proven intractable to conventional immunotherapy. The present proposal examines the novel and exciting result that CpG oligodeoxynucleotide (ODN) treatment significantly enhances host resistance to trypanosomiasis. The biological effects include a marked increase in host survival, decreased parasite burden, enhanced innate and adaptive immunity, and alterations in parasite cellular differentiation. Therefore, the aims of this proposal are to elucidate the kinetics, breadth and the underlying mechanism of optimal CpG ODN therapy of experimental trypanosomiasis. Specific Aim 1 examines CpG ODN-induced alterations in the infected host by measuring control of trypanosome tissue invasion, tissue-specific gene activation, innate immune cell stimulation, and parasite- specific B and T cell responses. Specific Aim 2 tests the mechanistic hypothesis that amplification of the TLR9-, MyD88- and IRF7-dependent Type I IFN (IFN-1/2) pathway underlies CpG ODN enhancement of host resistance. An alternative hypothesis is also presented in which CpG ODN treatment amplifies innate immune system production of Type II IFN (IFN-3) which regulates trypanosome long-slender to short-stumpy cellular differentiation and host resistance. Overall, these novel and exciting studies provide a new therapeutic approach to controlling African trypanosomiasis that avoids many of the issues complicating current therapy of this disease.Project Narrative This exploratory project proposes an innovative approach to the control or cure of African trypanosomiasis, a fatal human parasitic disease. Successful completion of the aims will enable public health officers to treat trypanosome infected individuals with CpG oligodeoxynucleotides which will activate critical components of the innate immune system to control the disease.